Amyotrophic lateral sclerosis (ALS) is an incurable, neurodegenerative disease characterized by progressive motor neuron loss, occurring in both sporadic and familial forms and leading to paralysis and ultimately death within 2-5 years after symptom onset. Currently, there are no effective treatments for ALS. Although the underlying pathogenic mechanisms of ALS remain unclear, protein aggregation is believed to be a major contributor to motor neuron death and subsequent disease progression. In this context, the most well- characterized system has been the assembly of Cu/Zn-superoxide dismutase 1 (SOD1) into neurotoxic oligomers and aggregates. The proposed study will investigate the effect of novel, recently-identified compounds called molecular tweezers (MTs) in cell culture and in a transgenic mouse model expressing the ALS-associated mutant, SOD1-G93A.The expected outcome is both enhanced understanding of the role of protein aggregation in ALS and establishing structure-activity relationships (SAR) for new MTs towards development of these compounds for disease-modifying therapy for ALS. MTs have been developed by the Bitan Laboratory as broad-spectrum, process-specific inhibitors of amyloidogenic proteins' self-assembly and toxicity. Initial in vitro data show that a lead MT called CLR01 inhibits both wild type and mutant SOD1 aggregation and dissociates pre-formed SOD1 fibrils. In collaboration with the Bitan group, the Wiedau-Pazos Laboratory found that CLR01 attenuates cell death in a neuronal cell line expressing the SOD1-G93A variant. These initial data suggest that MTs may be protective against motor neuron death in ALS via inhibition of aberrant aggregation of SOD1. Based on these data, I propose to examine novel MT derivatives in vitro and in cell culture to establish SAR of the key ionic groups and test the disease-modifying potential of the most promising derivative by evaluating its effect on life span, muscle strength, and neuropathology in a mouse model expressing SOD1-G93A.